Liquid handling

ABSTRACT

An analysis system has a first region in which sample materials are stored at an appropriate storage temperature and an analysis region which is maintained at a controlled and stabilized temperature higher than the temperature of the first region. Transfer mechanism for transferring a quantity of sample material from the first region for loading into an analysis cuvette in the analysis region includes a liquid handling probe that is mounted on a probe transport carriage, and a drive for moving the transport carriage between the first and second regions. The transport carriage includes a storage chamber connected to the liquid handling probe, thermal energy supplying means in heat exchange relation with the storage chamber, and thermal sensor means carried by the transport carriage. Means responsive to the thermal sensor supplies thermal energy to the transport carriage to maintain the storage chamber at substantially the same temperature as the analysis region.

This is a divisional of application Ser. No. 706,070, filed Feb. 27,1985, now U.S. Pat. No. 4,670,219.

This invention relates to liquid handling systems, and to apparatus forthe analysis of fluid samples, and has particular application toapparatus for the analysis of constituents of biological fluids such asblood.

Clinical analyzers are useful in performing a variety of analyses,including kinetic and endpoint analyses, by techniques such asabsorption, light scattering, and/or fluorescence. Many chemicalanalyses must be conducted at controlled and stable temperatures as theinvolved chemical reactions are temperature sensitive. In conventionalclinical analysis systems, for example, raw or dilute sample is mixedwith one or more reactants for analysis, and the resulting mixture ismaintained in an incubator region to bring the mixture to the desiredanalysis temperature, for example, 37° C., a temperature substantiallyhigher than the temperature at which sample and reagent materials areusually stored. Clinical analyzers of the centrifugal type, in general,utilize a multicuvette rotor assembly which has a centrifugal array ofspaced elongated radially extending cuvettes, each of which has an innerchamber for initially holding a first reactant which is frequently asample of blood or other biological fluid, and an outer chamber forinitally holding one or more different reactants. The two chambers areseparated by divider structure, and the reactants are transferred bycentrifugal force to an analysis region at the outer end of the cuvettefor mixing and reaction and subsequent analysis. Small quantities ofsample (2-20 microliters) typically are loaded into the inner chambersand reactants in quantities of up to about 200 microliters are loadedinto the outer chambers. After loading, each rotor is conventionallyincubated to equilibrate the rotor and the reactants in its severalcuvettes to analysis temperature, and after such incubation the contentsof the rotor are analyzed. In a typical analysis sequence, the rotorassembly is first spun at 100 rpm, then accelerated to about 4000 rpmfor about one second for transferring the reactants from the innerchamber, then braked for mixing the sample and reactants, and thenbrought up to an analysis speed (typically 500-1000 rpm) for analysis.

Such analyzers are commonly used for the analysis of biological fluidssuch as blood, blood plasma or serum components, and perform absorbancemode analyses for glucose, cholesterol, creatinine, total protein,calcium, phosphorous, enzymes, and the like; and fluorescence or lightscattering mode analyses for glucose, bile acids, phenytoin,pheophylline, gentamycin and the like.

In accordance with one aspect of the invention, there is provided ananalysis system which has a first region in which sample materials arestored at an appropriate storage temperature and a second region whichis maintained at a controlled and stabilized temperature higher than thetemperature of the first region. An analysis cuvette is in the secondregion, and transfer mechanism is provided for transferring a quantityof sample material from the first region for loading into the analysiscuvette in the second region. The transfer mechanism includes a liquidhandling probe that is mounted on a probe transport carriage, and adrive for moving the transport carriage between the first and secondregions. The transport carriage includes a storage chamber connected tothe liquid handling probe, thermal energy supplying means in heatexchange relation with the storage chamber, and thermal sensor meanscarried by the transport carriage. Means responsive to the thermalsensor supplies thermal energy to the transport carriage to maintain thestorage chamber at substantially the same temperature as the secondregion. Preferably, liquid sensor means of suitable type such asoptical, conductive or capacitive type is carried by the transportcarriage for sensing the presence of liquid in the region between thetip of the probe and the storage chamber. Liquid metering means isconnected to the transport carriage, and control means is provided foroperating the drive and metering means to draw a predetermined quantityof sample material for analysis into the probe and the storage chamberand to deliver the predetermined quantity to the analysis cuvette in thesecond region in temperature equilibrated condition.

In preferred embodiments, the transport carriage includes a thermal massin the form of a metal cantilever arm with the liquid handling probefixedly mounted at one end thereof, the temperature sensor embedded inthe metal arm and the thermal energy supplying means including heatingmeans distributed along the length of the cantilever arm in intimatethermal transfer relationship therewith. The storage chamber is anelongated tubular conduit embedded in the metal arm in coil form.

In a particular embodiment, sample and reagent materials are stored inthe first region, two probes are mounted on the carriage, the transportcarriage includes two storage chambers, one connected to each probe, andthe control means operates drive and metering means to drawpredetermined quantities of sample and reagent materials through theprobes and into the storage chambers and deliver the predeterminedquantities of sample and reagent materials to an analysis cuvette in thesecond region in temperature equilibrated condition. A plurality ofanalysis cuvettes are in the second region, together with an analysisstation and a transport mechanism for transporting analysis cuvettessequentially to the loading station where the cuvettes are loaded withsample and reagent materials and then to the analysis station forphotometric analysis of the mixture of sample and reagent materials.

In accordance with another aspect, the liquid handling probe is a metaltube that is secured in the transport carriage in a through channel thatincludes a threaded portion and a tapered shoulder at one end of thethreaded portion. Clamping means includes a clamping member that has athreaded body and a passage axially extending through the threaded bodythat is defined in part by a circumferential array of axially extendingfinger portions in the threaded body, each finger portion having atapered surface at one end thereof. When the clamping member isthreadedly secured in the through passage with the metal tube extendingthrough the axially extending passage in the clamping member body, thetapered end surfaces of the finger portions engage the tapered shoulderand cam the finger portions inwardly to clamp the metal tube in thesupport member. This arrangement facilitates individual adjustment ofeach probe to position the probe tips in precise aligned relation.

In accordance with another aspect of the invention, a liquid sensorsystem is provided that includes a tubular member of dielectric materialwith electrically conductive plate elements on opposite sides of thetubular member to form an electrical capacitor of capacitance value thatvaries as a function of the fluid in the tube. In a particularembodiment, the tubular member is connected in a series flow pathbetween a probe tip and a storage chamber in a transport carriage. Meansfor monitoring the capacitance value to provide an indication of thenature of the fluid in the probe and storage chamber includes means forcyclically charging and discharging the capacitor and monitoring thecharge (or discharge) rate of the capacitor to provide an indication ofthe type of fluid in the tubular member.

In preferred embodiments, the tubular member is of cylindricalconfiguration and the capacitor plate elements are elongated electrodesthat are plated on opposite sides of the tubular member, each electrodehaving an angular extent of about 90°. A variable frequency oscillatoris coupled to a capacitor charge control circuit for repetitivelycharging and discharging the capacitor, and means are provided foradjusting the frequency of the oscillator so that particular fluids maybe identified as a function of the rate of charge (or discharge) of thecapacitor which in turn is a function of the dielectric (and/orconductivity) characteristics of the fluid in the tube. The sensor tubemay be straight or of other shape and may be used in a variety of liquidsensing applications. In a particular embodiment, two such sensing unitsare mounted on the cantilever arm of the transport carriage betweenprobe inlets and storage chambers. In that embodiment, a multicuvetteanalysis assembly of long thermal time constant material is employed,and small (less than one cubic centimeter), precise, operator-selectedquantities of sample and reagent liquids are concurrently transferred(via the storage chambers) from supply containers to the analysiscuvette in a time interval of about one second, that time interval beingsufficient for those sample and reagent materials to be equilibrated tothe analysis temperature so that substantially no further thermalequilibration interval is needed. In that embodiment, the clinicalanalyzer is of the centrifugal type and uses a multicuvette rotor whichhas a circumferential array of spaced elongated radially extendingplural chamber cuvettes, each of which has an inner chamber forinitially holding a first reactant (frequently a sample of blood orother biological fluid), and an outer chamber for initially holding oneor more different reactants. After the rotor is loaded, the reactantsare transferred by centrifugal force to an analysis region at the outerend of the cuvette for mixing and reaction and subsequent analysis byphotometric or other appropriate analysis technique.

Preferred embodiments of the invention provide a system in which sampleand reagent are drawn concurrently through the probes and sensor tubesrespectively into serially connected storage chambers in a heatexchanger arm where the temperatures of the sample and reagent liquidsare rapidly increased from the relatively low storage temperature to thesubstantially higher analytical temperature so that the aspirated sampleand reagent liquids are rapidly equilibrated to the analyticaltemperature during the approximately one-second duration of the movementof the transport arm from the sample and reagent stations to the loadingstation where the pipetted volumes of sample and reagent are dispensedinto a thermally equilibrated analytical cuvette. As both the cuvetteand the reaction constituents are at the analytical temperature when theconstitutents are dispensed into the cuvette, no incubation interval isrequired for equilibration, and analysis of the loaded cuvettes maycommence as soon as filling of the operator specified cuvettes has beencompleted. Should either the sample or reagent sensor signal that sampleliquid or reagent liquids have not been properly drawn into the storagechambers, the loading sequence is terminated or otherwise rescheduled,the aspirated materials are flushed, and the system automaticallycommences the next transfer sequence.

Other features and advantages of the invention will be seen as thefollowing description of a particular embodiment progresses, inconjunction with the drawings, in which:

FIG. 1 is a diagrammatic and partly perspective view of portions of acentrifugal analyzer system in accordance with the invention;

FIG. 2 is a top plan view of portions of the analytical and storagecompartments of the analyzer shown in FIG. 1;

FIG. 3 is a sectional view taken along the line 3--3 of FIG. 2;

FIG. 4 is a top plan view of the transfer arm assembly of the analyzer;

FIG. 5 is a side elevational view of the transfer arm assembly andportions of its drive mechanism;

FIG. 6 is a front view of the transfer assembly;

FIG. 7 is a top plan view of the sample storage chamber coil;

FIG. 8 is a side elevational view of the sample storage chamber coilshown in FIG. 7;

FIG. 9 is a top plan view of the reagent storage chamber coil;

FIG. 10 is a side elevational view of the reagent storage coil shown inFIG. 9;

FIG. 11 is a top view of the sample and reagent storage coils in stackedspaced relation;

FIG. 12 is a side elevational view of the sample and reagent storagecoils in stacked spaced relation;

FIG. 13 is an end view of the stacked coils shown in top view FIG. 11;

FIG. 14 is a sectional view through the transfer arm taken along theline 14--14 of FIG. 5;

FIG. 15 is a sectional view of the transfer arm casting taken along theline 15--15 of FIG. 14;

FIG. 16 is a sectional view taken along the line 16--16 of FIG. 15;

FIG. 17 is a sectional view taken along the line 17--17 of FIG. 6;

FIG. 18 is a sectional view of the clamping bolt;

FIG. 19 is a side elevational view of the sample sensor tube;

FIG. 20 is a bottom view of the sensor tube shown in FIG. 17;

FIG. 21 is a sectional view taken along the line 21--21 of FIG. 20;

FIG. 22 is a bottom view of the sensor assembly taken along the line22--22 of FIG. 17;

FIG. 23 is a block diagram of control circuitry associated with thetransfer assembly; and

FIG. 24 is a schematic diagram of the liquid sensor circuitry.

DESCRIPTION OF PARTICULAR EMBODIMENT

With reference to FIGS. 1-3, the analysis system thereshown is of thecentrifugal type and has analytical compartment 12 and sample/reagentstorage compartment 14 that are separated by thermal isolation wall 16and surrounded by thermal insulation walls diagrammatically indicated at18. Disposed in analytical compartment 12 are a stack of analysis rotors20 of the type shown in co-pending application Ser. No. 615,644 filedMay 31, 1984 entitled CENTRIFUGAL ANALYZER ROTORS, now U.S. Pat. No.4,580,897 the disclosure of which is incorporated herein by reference.Rotors 20 in analystical compartment 12 are maintained at a precise userspecified analytical temperature of 25°, 30° or 37° C. (plus or minus0.3° C.) by a recirculating flow of temperature stabilized air throughcompartment 12 as described in greater detail in co-pending applicationSer. No. 706,072 filed concurrently herewith and entitled ANALYSISSYSTEM, now U.S. Pat. No. 4,708,886 the disclosure of which isincorporated herein by reference. Storage compartment 14 is maintainedat a temperature that is substantially cooler than analysis compartment,for example 14°-15° C. (plus or minus 2° C.) by a similarly circulatingstream of temperature stabilized air.

The supply of analysis rotors 20 are stored in analysis compartment 12in spaced stacked relation in feeder tower 22. Each rotor 20 provides acircumferential array of thirty-nine analysis cuvettes 24, each of whichhas two loading ports 26, 28. The rotors 20 are of a long thermal timeconstant ultraviolet transmitting plastic so that the lower rotors inthe stack in feeder tower 22 are at equilibration with the temperatureof the analysis compartment 12. Also in compartment 12 is loadingstation 30 at which is disposed an indexable rotor support table 32 thatis indexed by a stepper motor not shown; analysis station 34 thatincludes rotor support table 36 that is driven in rotation by a DC drive(not shown); park station 38 that includes a fixed rotor support table40; discard stack 42 that includes receiving post 44 on which usedrotors are received; and transport mechanism 46 for transporting rotors20 from station to station, mechanism including caliper assembly 48 thathas a pair of articulated arms that pick up and release rotors 20.Further details of this transport and rotor handling system may be hadwith reference to co-pending application Ser. No. 706,073 filedconcurrently herewith entitled CUVETTE HANDLING, now U.S. Pat. No.4,738,825 the disclosure of which is incorporated herein by reference.

Disposed in storage compartment 14 is reagent table 50 on which an arrayof twenty reagent containers 52 (each of twenty milliliters capacity)are disposed and moved past reagent station 54 by an indexing motor (notshown); and transport ring 56 which holds forty-four one-quartermilliliter sample cups 58 and is moved by indexing mechanism (not shown)past sample station 60. Isolation chamber 62 is movable between anoperative position (as shown in FIG. 1) in which flange 64 is seatedagainst isolation wall 16 and chamber 62 extends over the reagent andsample stations 54, 60, and a retracted position in which chamber 62 isretracted into analysis compartment 12 so that operator access may beobtained to reagent table 50 and sample ring 56 in storage compartment14.

Mounted for movement within isolation chamber 62 is transfer armmechanism 70 that carries pipette tubes 72, 74 at its forward end andhas a drive of the type shown in co-pending application Ser. No. 599,509filed Apr. 12, 1984 entitled LIQUID HANDLING, now U.S. Pat. No.4,761,268 the disclosure of which is incorporated herein by reference,for moving transfer arm 70 between reagent station 54, sample station60, wash station 76 disposed in isolation wall 16, and loading station30 where the tips of pipette tubes 72, 74 are aligned with cuvetteloading ports 26, 28.

Diluent (distilled water) is stored in reservoir 80 that is connected tometering pumps 82, 84 via three way valves 86, 88. Sample metering pump82 has a capacity of one hundred microliters and reagent metering pump84 has a capacity of two-hundred fifty microliters, and each meteringpump includes a piston that is driven by a precision stepping motor 90.Metering pump 82 is connected to probe 72 through tubing 92 andcantilever arm 70 and metering pump 84 is connected to probe 74 throughtubing 94 and arm 70.

Further details of the reagent, sample, wash and loading stations may beseen with reference to FIGS. 2 and 3. Isolation chamber 62 has a seriesof five aperture ports 96 in its bottom wall 98--apertures 96W beingaligned with wash station 76; aperture 96S being aligned with samplestation 60; aperture 96R being aligned with reagent station 54; andaperture 96X being aligned with the dry well 97 of the reagent container52. Transfer arm 70 is moved within isolation chamber 62 and the probes72, 74 are inserted through apertures 96 by the drive mechanism shown inFIG. 5. Wash station 76 has two cylindrical wells 93 for receiving thetips of pipette tubes 72, 74, each reagent container 52 has port 95 anddry well 97; and each sample cup 58 has a port 99.

Further details of pipette transfer assembly 70 may be seen withreference to FIGS. 4 and 5. The pipette transfer assembly includesaluminum casting arm 100 that has a length of about 12.5 centimeters, awidth of about 2.3 centimeters and a graduated depth to a dimension ofabout 1/2 centimeter at its forward end. Depending portion 102 at itsrear end is secured to upstanding drive member 104 by bolt 106 and dowelpins. The drive mechanism is of the type shown in the above referencedcopending patent application Ser. No. 599,509 and includes support frame108, stepping motor driven lead screw 110 and guide shaft 112. Drivemember 104 is pivotally mounted on support 108 by pivot shaft 114 whichdefines a pivot axis. Cam follower aperture 118 of drive member 104cooperates with cam 120 that is mounted on shaft 122 that is driven inrotation by a stepping motor (not shown) to provide an angular lift ofabout 11° of transport carriage assembly 70 between the solid line anddotted line positions shown in FIG. 5.

Twenty-four ohm silicon insulated heater 130 is adhesively secured tothe lower surface of aluminum arm 100 and connected via leads 132 toterminal block 134 that is mounted on support board 136 that is securedto arm 100 by fasteners 138, 140. Formed in casting 100 is socket 142(FIG. 5) which receives thermistor 144 (YSI 44032 precisionthermistor--30,000 ohms resistance at 25° C.) that is secured to board136 by stand off 146. Also mounted on board 136 is voltage regulator148, decoupling and power supply capacitors 150, 151, liquid sensorcircuits 152, 154 that are separated by copper shield 158, and liquidsensor assembly 160. Secured to the forward end of casting 100 byfasteners 162 (FIG. 6) is support block 164 which receives collet bolts166 that clamp pipette tubes 72, 74.

Cast within aluminum arm 100 are sample chamber coil 170 and reagentchamber coil 172, each of which is formed of nineteen gauge thin wallstainless steel tubing. As indicated in FIGS. 7 and 8, sample chambercoil 170 is of single turn configuration and extends from inlet 174along inclined transition 175 and parallel sections 176, 178, 180 tooutlet 182 and provides a chamber of about one-hundred microliterscapacity. Reagent coil 172, as shown in FIGS. 9 and 10, is of doubleturn configuration and extends from inlet 184 through two turns thatinclude parallel lengths 186, 188, 190, 192 and 194 to outlet 196 toprovide a chamber of about two-hundred fifty microliters capacity. Thesample and reagent coils 170, 172 are purged with nitrogen, crimpedshut, secured in parallel spaced relation as indicated in FIGS. 11 and12 by spacer members 198, disposed in a mold for casting in aluminumbody 100, details of the resulting cast assembly being shown in FIGS.14-16.

Further details of pipette support assembly may be seen with referenceto FIGS. 6, 17 and 18. Each pipette tube 72, 74 is a 3.7 centimeterslength of 21 gauge thin wall stainless steel tubing (about 0.8 mm outerdiameter). Two bores extend through collet block 164, the lower sectionof each bore being threaded to receive collet bolt 166 and having a 45degree cam surface 200; and upper portion of the bore being an enlargedcylinder 202 in which Tygon tube 204 is seated against smaller diameterintermediate shoulder 206. Collet bolt 166, as shown in FIG. 18, hashexagonal head portion 208, threaded body portion 210 with axiallyextending slots 212 that define spaced axially extending finger portions214 each of which has a 45° end surface 215, and a through bore 216 inwhich the stainless steel pipette tube is disposed with its upper endextending into Tygon tube 204, as indicated in FIG. 17. Each pipettetube 72, 74 may be vertically adjusted over a range of about 0.3centimeters as compensation for tolerance build up of the several partsof the pipette support assembly. Tightening of collet bolt 166 bringssurfaces 200 and 215 into engagement and flexes fingers 214 inwardly tosecurely clamp the pipette tube. The upper end of connector tube 204 isreceived on a cooperating projecting metal sleeve 218 of the sensorassembly 160.

Further details of liquid sensor assembly 160 may be seen with referenceto FIGS. 17 and 19-22. That sensing assembly includes molded urethanehousing 230 which supports tubular sample liquid sensor 232 and tubularreagent liquid sensor 234. Each liquid sensor is of the configurationshown in FIGS. 19-21 and includes a tube 236 of suitable glass such asCorning 8870, Corning 8940 or Kimble R6 formed in a semi-circle of aboutone centimeter radius with a stainless steel sleeve 218 adhesivelysecured at each end of glass tube 36. The tube 236S for sample liquidsensor 232 has an outer diameter of about 1/2 millimeter, an innerdiameter of about 1/4 millimeter, and defines a volume of about 1.5microliters. The tube 236R for reagent liquid sensor 234 has an outerdiameter of about 3/4 millimeter, and a somewhat smaller wall thicknessso that it defines a chamber volume of about six microliters. Formedalong the semicircular length of each tube 236 on opposite sides thereofare silver electrode plates 240, 242 (DuPont 7713 silver ink), each ofwhich has an angular extent of about 90° as indicated in FIG. 21.Capacitor plate 240 extends from plated cylindrical lead attachment area244 along a tube length of about two centimeters with its other end 246spaced about 3/4 millimeter from plated lead attachment cylinder 248 forcapacitor electrode 242, the other end 250 of electrode 242 beingsimilarly spaced about 3/4 millimeter from lead attachment cylinder 244.As indicated in FIGS. 17 and 22, lead 252 (No. 40 AWG) extends fromattachment cylinder 244 to connector 254 which protrudes from urethanehousing 230 (FIGS. 17 and 22); and a similar lead 256 extends fromattachment cylinder 248 to connector pin 258. Connector pins 254S and258S provide connections via support board 136 to sample sensor circuit152 while leads 254R and 258R provide similar connections to reagentsensor circuit 154.

Aspects of the control circuitry may be seen with reference to FIG. 23.In response to temperature signals from thermistor 144 applied viaconnector 134 to circuit 268 in system controller 270, circuit 268produces an output over lines 272 through connector 134 to energizeheater 130 and maintain aluminum pipette arm essentially at thetemperature of analytical compartment 12. The control circuitry alsoincludes cascaded shift registers 274, 276; and digital-to-analogconverters 278, 280. Circuit 282 of controller 270 generates a serialdata train signal over line 284 through buffer amplifier 286 to shiftregister 274; and in response to clock signals on line 288 suppliedthrough buffer 290, that serial data train is shifted through register274 and over line 292 to the cascaded shift register 276 to load shiftregisters 274, 276 with digital values. Those digital values specify asample value that is applied over lines 294 to digital-to-analog digitalconverter 278 and a reagent value that is applied over lines 296 todigital-to-analog converter 280.

Converter 278 provides an analog output through amplifier 298 andconnector 134 for application to input 300 of sample circuit 152 whilethe reagent control signal generated by digital-to-analog converter 280is applied through amplifier 298R and connector 134 as input 300R ofreagent circuit 154. Sample sensor capacitor 232 is connected to circuit152 through connectors 254S, 258S and reagent sensor capacitor 232R isconnected to circuit 154 through connectors 254R, 258R. Circuit 152provides an output on line 302S through buffer 304 to sample indicatorcircuitry 306 in controller 270 while circuit 154 produces an output atterminal 302R through amplifier 308 to reagent indicator circuitry 310in controller 270, and circuits 306, 310 may provide outputs to circuit282 to adjust the sample and reagent signals being applied to circuits152, 154.

Further details of the sample sensor circuitry may be seen withreference to the schematic diagram of FIG. 24 which shows the samplesensor hybrid integrated circuit 152 (the reagent sensor hybridintegrated circuit 154 being the same). The circuitry includes voltagecontrolled oscillator 320 that generates an unsymmetrical square waveoutput on line 322, the duration of the low portion of the square waveoutput on line 322 being variable as a function of the analog voltageapplied to input terminal 300 by digital-to-analog converter 278. Thesquare wave output on line 322 is applied through inverting comparator324 and diode 326 to sensor circuitry 330 to which capacitor 232 isconnected--in parallel with diode 332 between input 334 of operationalamplifier 336 and output 338--the voltage at input 334 of operationalamplifier 336 being controlled by the divider network of resistors 340,342.

When the output of oscillator 320 on line 322 goes low, diode 326 isforward biased thereby reverse biasing diode 328. Capacitor 232 chargesthrough resistor 344 at a rate proportional to its capacitance value andthe output of operational amplifier 336 (on line 338) ramps downward ata rate inversely proportional to the value of capacitor 232 from avoltage of about 19.6 volts (determined by the voltage provided bydivider network of resistors 340, 342).

The output voltage on line 338 is applied to comparator 346 which has athreshold established by the divider network of resistors 348 and 350,and when the voltage at output 338 falls below that value, comparator344 produces an output on line 352 which conditions the data input 354of latch 356.

When the output of oscillator 320 on line 322 goes high, a transition isapplied through level shifting circuit 358 as a clock pulse to latch 356to apply the flip flop data input at terminal 354 as an output on line302 updating the liquid information to controller 270 over line 302. Thehigh output from oscillator 320 is also applied through inverter 324 toreverse bias diode 326, allowing diode 328 to be forward biased andestablishing a discharge current path for capacitor 232--capacitordischarging and the voltage at operational amplifier output 338increasing until diode 332 becomes forward biased, thus limiting theoutput voltage at line 338 to about 19.8 volts and re-establishing theinitial condition in the sensor capacitor 232 at the beginning of eachcharge cycle.

This circuitry thus provides continuous monitoring of the fluid in tube236 of capacitor 232 and provides signals to controller 270 throughbuffer 304 (308). The system may establish fixed analog values that areprovided by converters 278, 280 (and thus monitor the fluid in eachcapacitor tube for a particular type--a qualitative-type determination)or the system may vary the analog value to determine the type of fluid(a quantitative-type determination) drawn into the tube during eachtransfer cycle.

Sample capacitor 232 has a value of about two picofarads when its tube220S is filled with air, a value of about 4.2 picofarads when its tube220S is filled with diluent, and a value of about 5.5 picofarads whenits tube 220S is filled with serum; and reagent capacitor 234 has acapacitance value of about 3.5 microfarads when its tube 220R is filledwith air a value of about 7.7 picofarads when its tube 220S is filledwith diluent, and a value of about 9.5 picofarads when its tube isfilled with reagent. Thus the capacitance value of each sensor capacitorincreases significantly when sample liquid or reagent liquid (as thecase may be) is in its tube 220. These capacitance values arerepetitively monitored (at rates in excess of ten thousand times persecond) by measuring the rate at which the capacitors 232, 234 charge inresponse to negative transitions from voltage controlled oscillators320. The frequencies of the square wave output from oscillators 320 arespecified and changed by controller 270 through the shift registers 274,276 and digital-to-analog converters 278, 280, to provide charge timeduration values selected to provide triggering outputs from comparator346 to latch 356 that indicate the type of fluid in the sensor tubes220S and 220R.

In system operation, drive 110 positions arm 100 at the reagent andsample stations 54, 60 and drive 122 inserts the probe tips intocontainers 52, 58 at those stations. The liquid handling system pumps 82and 84 draw sample and reagent concurrently through pipettes 72, 74, andthe two capacitor sensor tubes 220S, 220R respectively into the seriallyconnected storage chambers 172, 174 in the aluminum arm 100 where thetemperatures of the sample and reagent liquids rapidly increase from therelatively low storage temperature of compartment 14 to thesubstantially higher operator selected temperature (25°, 30° or 37° C.)of analytical compartment 12 so that the aspirated sample and reagentliquids are rapidly equilibrated to the analytical temperature duringthe approximately one second duration of the movement of the transportarm 70 from the sample and reagent stations 60 and 54 to the loadingstation 30 where the pipetted volumes of sample and reagent aredispensed into the analytical cuvette 24 that is at the equilibratedtemperature of the analytical compartment 12. The cuvette 24 and thereaction constituents thus are at the analytical temperature when theconstitutents are dispensed into the cuvette (no incubation intervalbeing required for equilibration) and the transport calipers 48 may movethe loaded analysis rotor from loading station 30 to analysis station 34as soon as filling of the operator specified cuvette regions has beencompleted. Should sample or reagent sensor circuit 154 or 156 signalcontroller 270 that sample liquid or reagent liquids have not beenproperly drawn into the storage chambers, controller 270 terminates orotherwise reschedules the loading sequence, the aspirated materials aredispensed into the wash station 76, pipettes 72, 74 are flushed and thenext transfer sequence is automatically commenced.

While a particular embodiment of the invention has been shown anddescribed, various modifications will be apparent to those skilled inthe art, and therefore it is not intended that the invention be limitedto the disclosed embodiment, or to details thereof, and departures maybe made therefrom within the spirit and scope of the invention.

What is claimed is:
 1. A method of operating an analysis system thathasa first region in which sample materials are adapted to be stored. asecond region in which an analysis cuvette is adapted to be disposed,transfer mechanism including a liquid handling probe, a probe transportcarriage on which said liquid handling probe is mounted, a drive formoving said transport carriage between said first and second regions,said transport carriage including a solid body of thermally conductivematerial, sample material storage chamber structure embedded in saidbody and connected to said liquid handling probe, thermal energy supplymeans in heat exchange relation with said body, and thermal sensor meanscarried by said transport carriage, and liquid metering means connectedto said storage chamber, said method comprising the steps of maintainingsaid first region at an appropriate storage temperature, disposingsample materials in said first region, disposing an analysis cuvette insaid second region, maintaining said second region at an appropriateanalysis temperature at least about 10° C. higher than said storagetemperature such that said analysis cuvette is equilibrated to saidanalysis temperature, supplying thermal energy to said thermal energysupply means in response to said thermal sensor means to maintain saidtransport carriage body at said analysis temperature, and operating saiddrive and metering means to draw a predetermined quantity fo samplematerial for analysis from said first region through said probe intosaid storage chamber and to deliver said predetermined quantity ofsample material to said analysis cuvette in said second regionequilibrated in temperature to said analysis temperature in a timeinterval of about one second.
 2. The method of claim 1 wherein saidtransport carriage body also includes reagent storage chamber structureto which a reagent handling probe and said metering means are connectedand said method further includes the steps of disposing reagent materialin said first region, andoperating said metering means to concurrentlydraw predetermined quantities of sample and reagent materials from saidfirst region into said sample and reagent storage chamber structure andto concurrently deliver said predetermined quantities of sample andreagent materials to said analysis cuvette in said second regionequilibrated in temperature to said analysis temperature in a timeinterval of about one second.
 3. A liquid sensor system comprising atubular member of dielectric material for connection in a flow path of aliquid to be sensed, electrically conductive electrode elementsfixedly-mounted on opposite sides of said tubular member to form anelectrical capacitor of capacitance value that varies as a function ofthe fluid in said tube, and means for monitoring the capacitance valueto provide an indication of the nature of the fluid in said probe andstorage chamber, said capacitance monitoring means including means forrepetitively monitoring the rate of change of charge on said capacitorto provide an indication of the type of fluid in said tubular member. 4.The system of claim 3 wherein said tube is of cylindrical configurationand said electrode elements are elongated electrodes that are platedalong opposite sides of said tube, each said electrode having an angularextent of about 90°.
 5. The system of claim 3 and further including avariable frequency oscillator for repetitively discharging saidcapacitor, and means for adjusting the frequency of said oscillator as afunction of conductivity characteristics of the liquid to be monitored.6. The system of claim 3 and further includingstructure defining a firstregion in which sample materials are adapted to be stored at anappropriate storage temperature, structure defining a second region inwhich an analysis cuvette is adapted to be disposed at an appropriateanalysis temperature, transfer mechanism for transferring a quantity ofsample material from said first region for loading into an analysiscuvette in said second region, said transfer mechanism including aliquid handling probe, a probe transport carriage on which said liquidhandling probe and said tubular member are mounted, a drive for movingsaid transport carriage between said first and second regions, saidtransport carriage including a storage chamber connected to said liquidhandling probe through said tubular member, thermal energy supplyingmeans in heat exchange relation with said storage chamber, and thermalsensor means carried by said transport carriage, means responsive tosaid thermal sensor for supplying thermal energy to said thermal energysupplying means, liquid metering means connected to said transportcarriage, and control means for operating said drive and metering meansto draw a predetermined quantity of sample material for analysis intosaid probe and said storage chamber and to deliver said predeterminedquantity to an analysis cuvette in said second region in temperatureequilibrated condition.
 7. The system of claim 6 wherein said transportcarriage includes a body of thermally conductive material, said storagechamber structure being embedded in said body and said liquid handlingprobe and said tubular member being fixedly mounted at one end of saidbody.
 8. The system of claim 7 wherein said temperature sensor embeddedin said body and said thermal energy supplying means includes heatingmeans distributed along the length of and in intimate thermal engagementwith said body.
 9. The analysis system of claim 8 wherein said storagechamber is an elongated tubular conduit that is disposed within saidbody and is connected between said metering means and said tubularmember.
 10. The system of claim 6 wherein said probe, said liquid sensortubular member, and said storage chamber tube have similar innerdiameters and the inner diameter of each is less than one millimeter.11. The analysis system of claim 6 wherein said tubular member is ofcylindrical configuration and said electrically conductive electrodeelements are elongated electrodes that are plated along opposite sidesof said tubular member, each said electrode having an angular extent ofabout 90°.
 12. The system of claim 11 wherein said capacitancemonitoring means includes means for repetitively charging said capacitorcomprising a variable frequency oscillator, and means for adjusting thefrequency of said oscillator to identify the liquid to be transferredfrom said first region to said second region as a function of itsconductivity characteristics.
 13. The system of claim 6 and furtherincluding two liquid sensor means carried by said transport carriage,each said liquid sensor means including a said tubular member connectedto a corresponding probe for sensing the presence of liquid in theregion between the tip of said probe and its storage chamber.
 14. Thesystem of claim 13 wherein said probes, said liquid sensor tubularmembers, and said storage chamber tubes have inner diameters of similarvalues and the inner diameter of each is less than one millimeter. 15.The system of claim 13 wherein each said liquid handling probe is anelongated metal tube, and further including a probe support portion onsaid body at one end thereof, said support portion having two throughchannels for receiving said metal tubes and cooperating tube clampingmeans that permits the axial position of each said elongated metal tubein said support portion to be axially adjusted.
 16. The system of claim15 wherein each said tubular member is of cylindrical configuration andsaid electrically conductive electrode elements are elongated electrodesthat are plated along opposite sides of each said tubular member, eachsaid electrode having an angular extent of about 90°.
 17. The system ofclaim 16 wherein said capacitance monitoring means includes means forrepetitively charging said capacitor comprising a variable frequencyoscillator, and means for varying the frequency of said oscillator toidentify the liquid to be transferred from said first compartment tosaid second compartment as a function of its dielectric characteristics.